This FOA, issued by the National
Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, invites
Research Project Grant (R01) applications that propose to investigate the
early origins of cystic fibrosis (CF) lung disease and the mechanisms
involved in development and progression of pulmonary abnormalities in young
children with this condition. Studies may explore novel strategies for
detecting early lung disease in infants and young children with CF, including
minimally invasive biomarkers and/or imaging approaches, and utilize these
methods to elucidate the molecular and cellular mechanisms of early lung
disease onset and progression. The ultimate goal is development of novel
approaches for diagnosis, prevention, and treatment of early CF lung disease.

Key Dates

Posted Date

August 19, 2011

Open Date (Earliest Submission Date)

December 11, 2011

Letter of Intent Due Date

December 12, 2011

Application Due Date(s)

January 11, 2012, by 5:00 PM
local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

May/June, 2012

Advisory Council Review

August 2012

Earliest Start Date(s)

September 30, 2012

Expiration Date

January 12, 2012

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in
the SF
424 (R&R) Application Guide except where instructed to do otherwise (in
this FOA or in a Notice from the NIH
Guide for Grants and Contracts). Conformance to all requirements
(both in the Application Guide and the FOA) is required and strictly enforced.
Applicants must read and follow all application instructions in the Application
Guide as well as any program-specific instructions noted in Section
IV. When the program-specific instructions deviate from those in the Application
Guide, follow the program-specific instructions.

Applications that do not comply with these
instructions may be delayed or not accepted for review.

Cystic fibrosis (CF) is the most common life-shortening
autosomal recessive disorder in those persons with European ancestry. Repeated
infections, lung damage, and respiratory failure are the most common
complications leading to death. In the twenty years since discovery of the
gene encoding CFTR, there has been significant progress in understanding the
structure and function of CFTR, how mutations disrupt CFTR function, and the
infection and inflammation that destroy the CF lung. Advances in survival have
been realized with treatments directed at established disease in older children
and adults, however we now have an opportunity to preempt and prevent CF lung
disease earlier. Mechanisms and potential reversal of the early origins of CF
lung disease have scarcely been explored.

Emerging evidence suggests that lung disease (namely,
bronchiectasis, infection) begins early in infancy (3 months of age) and is
initially “silent,” with substantial airways disease existing in the absence of
overt signs and symptoms of a progressive disease process. Intervening during
infancy or early childhood could potentially delay or prevent irreversible lung
disease and improve CF survival and quality of life, but this will require early
detection of disease in pre-symptomatic infants and young children. Hence, early
markers of lung disease and appropriate end-points to establish disease
severity, course of disease, and response to therapy are needed. The new
frontier in CF is to detect and characterize disease in infants and young
children before clinically observable signs or symptoms, at stages where
irreversible lung damage is minimal and therapeutic intervention may be most
effective. It is currently unclear how to detect, much less treat, this
pre-symptomatic disease of infants and young children, and there is no clinical
trial evidence base to guide therapeutic strategies in infants and children
less than 6 years of age. Thus, better knowledge of pathogenesis in the early
stages of life is also needed for identification of new therapeutic targets and
outcome measures. Definition of the initial pathologic events will likely
reveal improved strategies to delay or prevent early airway infection,
inflammation, and structural remodeling (bronchiectasis), the major causes of
morbidity and mortality in CF.

Universal newborn screening, conducted within the first days
of life, now allows identification of most pre-symptomatic infants with CF by 2
to 6 weeks of age compared to 2 to 3 years previously. This screening provides
unprecedented opportunities for identifying pre-symptomatic cases of CF,
investigating mechanisms of CF lung disease at a very early stage (under 6
years of age), monitoring the progress of the disease longitudinally, and
intervening in productive ways before irreversible lung disease develops. New
technologies are now available to elucidate features of CF physiology, which
can be adapted for use in infants. Potential lung disease biomarkers are known
but need further validation to predict development and progression of CF lung
disease. New animal models of the CF pulmonary phenotype are also in place and
are providing insights that can inform human studies. These powerful new
capabilities invite a new strategy of primary prevention and/or mitigation of
CF progression in infancy and early childhood.

Research Objectives

To promote better understanding of early CF, this initiative
will support up to 6 R01 grants that focus on the preclinical and early stages
of lung involvement in this disease (birth to 6 years of age). The goals are
to characterize the early origins of CF lung disease, elucidate mechanisms of disease
development and progression, and identify targets and strategies for early
interventions that will mitigate the pulmonary manifestations of CF. These
objectives will likely require novel strategies for detection of early lung
disease in infants and young children with CF, including minimally invasive
biomarkers and/or imaging approaches that will predict the development and
progression of pulmonary abnormalities and outcomes, as well as investigation of
specific pathways related to these abnormalities that may be targeted by early
interventions. Individual or combinations of relevant biological mechanisms
may be studied, including but not limited to inflammation, infection, airway
dehydration, ion transport, and abnormal epithelial function. Technologies for
examining anatomic changes in early CF lungs (biomarkers and/or new imaging
technologies) must be proposed in conjunction with mechanistic studies.
Studies of humans will be required. Limited (not to exceed 25% of the proposed
research scope) complementary studies conducted using newer animal models of CF
may also be proposed. This program strongly encourages the forging of new
collaborations involving multidisciplinary teams of investigators from a broad
array of fields to develop novel strategies to elucidate mechanisms of early
lung disease. Clinicians are encouraged to partner with experts in imaging
and/or basic science to study structural changes in concert with functional
abnormalities. Of particular interest are innovative studies using biological
samples derived from CF infants and young children to detect gene x environment
interactions that predict early lung disease (e.g., gene expression, proteomic,
or metabolomic approaches); novel imaging approaches to detect early reversible
lung disease (e.g., optical coherence tomography, etc.); and measures of
altered airway defense and physiologic function (e.g., host-microbiome
interactions, inflammation, repair, hydration, mucus properties, ion transport,
progenitor cell dysfunction, etc).

Through this program, we expect to gain mechanistic
understanding of the early origins of CF lung disease and to develop predictors
and markers of its onset, progression, and severity in CF infants and young
children. Additional goals include the identification of modifiable risk
factors and of potential new targets for early intervention. Development of
technologies and tools for characterizing lung disease that will enable examination
of early CF lung disease pathogenesis, onset, and progression in humans will be
allowed if required to address specific biological or clinical questions being
asked in the research proposal. RFA meetings will be held yearly to enable
investigators to share their successes and challenges, encourage
collaborations, and promote sharing and consistency of data collection and
analyses across the sites where appropriate.

SELECTED RESEARCH EXAMPLES:

Research topics of interest include, but are not limited to
those listed below:

Development of innovative strategies to detect and monitor early CF
lung disease in humans and further elucidate mechanisms of origin and
progression.

Identification of biomarkers (including minimally and
non-invasive markers) of early CF lung disease onset, progression, and severity
that reflect CF pathophysiology or predict response to treatment.

Identification of novel, safe imaging approaches to detect and
track early CF airway abnormalities in humans.

Investigation of the associations of biomarkers and imaging
measures with the onset, progression, and clinical outcome of pulmonary disease
in infants and young children.

Evaluation of the magnitude and distribution of early CF lung
disease using imaging technologies in concert with measures of physiologic
function to interrogate and dissect heterogeneity and reversibility of early CF
lung disease.

Development of improved minimally invasive or non-invasive
methods for determining early infection, injury, and impaired clearance in the
lung (i.e., imaging and sputum/blood surrogate markers).

Exploration of the relationship and contribution of genotype,
genetic modifiers, host-microbiome interactions, inflammation, and remodeling
to functional and phenotypic consequences of early CF lung disease using an
integrative approach.

Investigation of specific pathways and interventions related to
the disease-associated abnormalities.

Determination of strategies that reverse early radiologic
findings such as bronchiectasis.

Exploration of the role of CF modifier genes and associated
variants (identified by GWAS) in early CF disease pathogenesis and disease
outcome using integrated approaches with a focus on drugable targets and
development of potential pharmacologic interventions via these pathways.

Investigation in CF animal models of specific pathways and early
interventions related to the disease-associated abnormalities being
investigated in human studies.

Section II. Award Information

Funding Instrument

Grant

Application Types Allowed

New
The OER
Glossary and the SF 424 (R&R) Application Guide provide details on
these application types.

Funds Available and Anticipated Number of Awards

The NHLBI intends to commit $3.0
million total costs in FY 2012 to fund up to six awards, with a total cost
commitment of $12.0 million over the four year period.

Award Budget

Application budgets are limited
to a maximum of $400,000 direct costs (exclusive of first tier consortium
F&As) in any year. Budgets must reflect actual needs of the proposed
project.

Award Project Period

The scope of the proposed project
should determine the project period up to a maximum of four years.

NIH grants policies as
described in the NIH Grants
Policy Statement will apply to the
applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for NIH support as Public or Private
Institutions of Higher Education:

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to
apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant organizations must complete the following
registrations as described in the SF 424 (R&R) Application Guide to be
eligible to apply for or receive an award. Applicants must have a valid Dun and
Bradstreet Universal Numbering System (DUNS) number in order to begin each of
the following registrations.

All Program Directors/Principal Investigators (PD/PIs) must
also work with their institutional officials to register with the eRA Commons
or ensure their existing eRA Commons account is affiliated with the eRA Commons
account of the applicant organization.

All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least four (4) weeks prior to the application due date.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director/Principal
Investigator (PD/PI) is invited to work with his/her organization to develop an
application for support. Individuals from underrepresented racial and ethnic
groups as well as individuals with disabilities are always encouraged to apply
for NIH support.

Applicant organizations may submit more than one
application, provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA
that is essentially the same as one currently pending initial peer review
unless the applicant withdraws the pending application. NIH will not accept any
application that is essentially the same as one already reviewed.

Section IV. Application and Submission
Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and
Form of Application Submission

It is critical that applicants follow the instructions in the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part
1. Overview Information, prospective applicants are asked to submit a
letter of intent that includes the following information:

The forms package associated with this FOA includes all
applicable components, mandatory and optional. Please note that some
components marked optional in the application package are required for
submission of applications for this FOA. Follow all instructions in the SF424
(R&R) Application Guide to ensure you complete all appropriate “optional”
components.

Page Limitations

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Resource Sharing Plan

Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies; GWAS) as provided in the SF424
(R&R) Application Guide.

Appendix

Do not use the appendix to circumvent page limits.
Follow all instructions for the Appendix as described in the SF424 (R&R)
Application Guide.

Foreign Institutions

Foreign (non-US) institutions must follow policies described
in the NIH
Grants Policy Statement, and procedures for foreign institutions described
throughout the SF424 (R&R) Application Guide.

3. Submission Dates and Times

Part
I. Overview Information contains information about Key Dates. Applicants
are encouraged to submit in advance of the deadline to ensure they have time to
make any application corrections that might be necessary for successful
submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants
across all Federal agencies. Applicants must then complete the submission
process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants
administration.

Applicants
are responsible for viewing their application in the eRA Commons to ensure
accurate and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:
All PD/PIs must include their eRA Commons ID in the Credential field of
the Senior/Key Person Profile Component of the SF 424(R&R) Application
Package. Failure to register in the Commons and to include a valid PD/PI
Commons ID in the credential field will prevent the successful submission of an
electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the Central Contractor Registration (CCR). Additional
information may be found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by NHLBI, NIH. Applications that are
incomplete and/or nonresponsive will not be reviewed.

Investigate mechanisms of early CF lung disease in humans and
explore biomarkers suitable for use in infants and young children that link to
clinically meaningful outcomes.

Describe the relevance of any proposed in vitro human CF studies
to the in vivo disease state.

Animal studies, if included, must be complementary to the
proposed human research, utilize newer models (e.g., pig and ferret newer mouse models), and
address mechanistic or therapeutic questions that cannot be addressed directly
in humans. The animal work may not exceed 25% of the proposed research scope
as assessed by program staff of the Division of Lung Diseases or the grant may
be returned to the applicant.

The program strongly encourages the forging of new
collaborations involving teams of investigators from a broad array of fields.
This translational work may span areas from imaging to genetics to cell
physiology to disease. Clinicians are encouraged to partner with experts in
imaging and/or basic science to characterize structural changes in concert with
functional abnormalities.

FOA meetings will be held yearly to enable investigators to
share their successes and challenges, encourage collaborations, and promote
sharing and consistency of data collection and analyses across the sites where
appropriate. Investigators should plan to attend grantee meetings in the
Bethesda MD area and budget accordingly.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral research
are evaluated for scientific and technical merit through the NIH peer review
system.

Overall Impact

Reviewers will provide an overall impact/priority score to
reflect their assessment of the likelihood for the project to exert a
sustained, powerful influence on the research field(s) involved, in
consideration of the following review criteria and additional review criteria
(as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

Investigator(s)

Are the PD/PIs, collaborators, and other researchers
well suited to the project? If Early Stage Investigators or New Investigators,
or in the early stages of independent careers, do they have appropriate
experience and training? If established, have they demonstrated an ongoing
record of accomplishments that have advanced their field(s)? If the project is
collaborative or multi-PD/PI, do the investigators have complementary and
integrated expertise; are their leadership approach, governance and
organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be
managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact/priority score, but will
not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46, the
committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact/priority score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents
special opportunities for furthering research programs through the use of
unusual talent, resources, populations, or environmental conditions that exist
in other countries and either are not readily available in the United States or
augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by the NHLBI, in
accordance with NIH peer
review policy and procedures, using the stated review
criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review), will be discussed and assigned an overall
impact/priority score.

Will receive a written critique.

Applications will be assigned to the appropriate NIH
Institute or Center. Applications will compete for available funds with all
other recommended applications submitted in response to this FOA. Following
initial peer review, recommended applications will receive a second level of
review by the NHLBI Advisory Council. The following will be considered in
making funding decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the
PD/PI will be able to access his or her Summary Statement (written critique)
via the eRA
Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section
IV.5. Funding Restrictions. Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the
extent considered allowable pre-award costs.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH Grants Policy
Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants
Policy Statement for additional information on this reporting requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Each IC may add information describing the topics for which
applicants should contact staff. ICs cannot require prior approvals in this
section.

Awards are made under the authorization of Sections 301 and
405 of the Public Health Service Act as amended (42 USC 241 and 284) and under
Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.